Ordinarily, when minute ventilation increases, the partial pressure of end tidal CO2 (PETCO2) decreases and partial pressure of end tidal O2 (PETO2) increases. U.S. Pat. No. 6,622,725, (Fisher et al.), describes fixing fresh gas flowing into a partial rebreathing circuit, which in that instance was also a sequential gas delivery circuit, in order to maintain constant PETCO2 in the face of increases in minute ventilation on the part of the subject. Canadian Patent Application 2,346,517 (Fisher et al.) also describes means of keeping PETO2 constant at a given attained level despite increases in minute ventilation. None of these documents disclose means to set gas flows and gas concentrations into a circuit to attain a target end tidal fractional concentration of CO2 (FTETCO2) and/or a target end tidal fractional concentration of O2 (FTETO2) for a given minute ventilation ({dot over (V)}E), that is different from initial FTETCO2 and FTETO2.
Providing a level of control that permits attaining a target end tidal fractional concentration of CO2 (FTETCO2) and/or a target end tidal fractional concentration of O2 (FTETO2) for a given minute ventilation ({dot over (V)}E), that is different from initial FTETCO2 and FTETO2.can be used for a number of applications. For example, one such application is measuring cerebrovascular reactivity. Cerebral blood flow (CBF) is closely regulated by metabolic demands of the brain tissue. CBF also responds to changes in arterial PCO2 and PO2. The extent of the change in CBF in response to a stimulus is termed cerebrovascular reactivity (CVR). CVR may be a sensitive indicator of abnormal vessels such as vascular dysplasia or tissue abnormalities such as brain swelling and cancer. Quantitatively mapping CVR throughout the brain using imaging techniques such as magnetic resonance imaging (MRI) could identify areas of abnormal CVR.
Brain blood vessel diameter responds to changes in blood PO2 as well as blood PCO2. Blood PO2 and blood PCO2 are strongly tied to end tidal concentrations of O2 and CO2 respectively. Present methods of inducing high PETCO2 control PETO2 poorly and do not control PCO2 and PO2 independently.
There are several current methods that are known for changing blood PCO2 and PO2 via control of the gas concentrations in the lungs.
A: Breath-holding
One method for inducing changes in PCO2 during Magnetic Resonance Imaging (MRI) is breath-holding. As there is a rapid drift in the baseline MRI signal, changes in MRI signal resulting from changes in brain blood flow can be detected only by rapidly alternating the stimulus between “control” and “test” values. With respect to PCO2, this requires rapid step changes in PCO2, preferably maintaining PO2 constant. Cycle times of 3 min have been reported by Vesely et al (1) to be suitable, but shorter cycle times would be preferred. Breath-holding induces an increase in PCO2 but it is not well suited to measuring CVR. The rise in blood PCO2 during breath-holding is very slow as it is dependent on body CO2 production ({dot over (V)}CO2), which is small compared to body capacitance for CO2. During breath holding, alveolar PO2 declines progressively. As CO2 production, CO2 capacitance and the tolerable breath-holding time varies from subject to subject, so will the final blood PCO2 and PETO2. As there is no gas sampling during breath-holding the blood PCO2 and PO2 is unknown for the duration of the breath-hold so it is not possible to relate the MRI signal strength to PCO2 or PO2, a requirement for the calculation of CVR. The changes in lung and blood PCO2 during breath-holding are an exponential function with time. Therefore breath holding time is a poor variable to use to quantitate the strength of the stimulus.
B: Inhaling CO2 
A second traditional method of changing PCO2 is inspiring gas mixtures containing CO2 via a facemask. This is known to result in a highly variable ventilatory response between subjects leading to a large variability in PETCO2. Furthermore, inhaling CO2 changes the minute ventilation ({dot over (V)}E) resulting also in variability in blood PO2. Oxygen is a potent vasoconstrictor and confounds the interpretation of the relationship between PCO2 and brain blood flow.
Therefore, neither breath-holding nor inhaling a gas mixture containing CO2 provide suitable conditions for a consistent, repeatable quantitative test for CVR.
C: Gas Forcing
Since the effects of inhaling a CO2-containing gas mixture on increasing PCO2 can be overcome by increasing minute ventilation, one can introduce a feedback loop to adjust the inhaled PCO2 to effect a target PETCO2. This is referred to as “gas forcing” (2). Gas forcing has been shown to be effective in imposing target PETO2 and target PETCO2 independent of minute ventilation. However, it does have some drawbacks with respect to measuring CVR:
Gas forcing depends on a feedback loop. Feedback loops can have inherent instability depending on the gain and time constant of the system, and are prone to drift and oscillation of end-tidal values.
Gas forcing is usually applied in a chamber or requires a hood over the head. As such, there is a large volume of gas that needs to be replaced rapidly for each change in inspired PCO2. This necessitates very large flows of gases and very precise flow controllers for each gas (such as N2, O2 and CO2 if only these gases are controlled). This is very expensive and cumbersome, and an error which leads to presentation of pure N2 or pure CO2 could be deadly.
Gas forcing requires the construction of a special chamber that is not available commercially and has been custom built for research purposes. This is available only in a few places in the world.
The requirement for specific air-tight chambers, large gas flow controllers, massive volumes of gases, and complex computer control algorithms makes gas forcing too cumbersome to be suitable for use in a radiology, MRI and ophthalmology suites.
The time constant for changes in alveolar gas concentrations is too long to be suitable for use with MRI.
D: Sequential Gas Delivery Method:
A more recent method introduced by Vesely et al. (1) solved some of these problems. They used O2 flow to a sequential gas delivery (SGD) circuit to produce rapid changes in PETCO2 between two known levels (30-50 mmHg). (A SGD circuit provides (at least) two gases through two breathing circuit limbs. The gas from the first limb (G1) is provided first, and if the subject's breathing exceeds the available first gas, the balance of that breath is made up of the second gas (G2). The second gas may be previously exhaled gas collected in a reservoir on the second limb.) To reduce PCO2, they asked their subjects to hyperventilate while providing large O2 flows into the SGD. To raise the PCO2, they provided a bolus of CO2 by briefly changing the composition of the gas entering the circuit and then maintained the raised PCO2 by controlling the flow into the SGD. While this allowed transitions to a new PETCO2, the lowering and raising of O2 flows into the circuit to control PETCO2 and the required changes in {dot over (V)}E cause alveolar, and thus end tidal, O2 concentrations to change during the protocol despite near constant inspired O2 concentration. For example, when O2 flow is restricted in order to keep the PETCO2 high, the PETO2 tends to drift down (as O2 consumption stays constant in the face of reduced O2 delivery). When subjects hyperventilate to lower the PETCO2 the increased O2 flow into the circuit results in a rise of PETO2 (as O2 consumption stays constant and O2 delivery is increased). The changes in blood PO2 have an effect on the MRI signal independent of brain blood flow confounding the interpretation with respect to blood flow.
There are additional practical problems with this method:
Subjects must change their {dot over (V)}E frequently during the protocol. It may be difficult for most people to comply adequately with this.
Not adequately following breathing instructions results in not meeting target PCO2 values
Not responding to breathing instructions quickly enough invalidate the MRI data.
The method of Vesely et al uses 2 gases and the manipulation of flow into the circuit to change end tidal CO2 values. With this method, if the total flow is set, then
varying the inspired PCO2 changes the inspired PO2.
PETO2 cannot be determined independently of PETCO2.
PETO2 and PETCO2 cannot be varied independently.
Reference List
    (1) Vesely A, Sasano H, Volgyesi G, Somogyi R, Tesler J, Fedorko L et al. MRI mapping of cerebrovascular reactivity using square wave changes in end-tidal PCO2.Magn Reson Med 2001; 45(6):1011-1013.    (2) Robbins P A, Swanson G D, Howson M G. A prediction-correction scheme for forcing alveolar gases along certain time courses. J Appl Physiol 1982; 52(5):1353-1357.